NM_000251.3(MSH2):c.1840G>T (p.Gly614Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 4, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001188274.5

Allele description [Variation Report for NM_000251.3(MSH2):c.1840G>T (p.Gly614Ter)]

NM_000251.3(MSH2):c.1840G>T (p.Gly614Ter)

Gene:

MSH2:mutS homolog 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_000251.3(MSH2):c.1840G>T (p.Gly614Ter)

HGVS:

NC_000002.12:g.47475105G>T
NG_007110.2:g.76982G>T
NM_000251.3:c.1840G>TMANE SELECT
NM_001258281.1:c.1642G>T
NP_000242.1:p.Gly614Ter
NP_001245210.1:p.Gly548Ter
LRG_218t1:c.1840G>T
LRG_218:g.76982G>T
NC_000002.11:g.47702244G>T
NC_000002.11:g.47702244G>T
NM_000251.1:c.1840G>T
NM_000251.2:c.1840G>T

Protein change:

G548*

Links:

dbSNP: rs1380847972

NCBI 1000 Genomes Browser:

rs1380847972

Molecular consequence:

NM_000251.3:c.1840G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258281.1:c.1642G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001355296	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 21, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002717039	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001355296

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 21, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002717039

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 4, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Lynch-like syndrome is as frequent as Lynch syndrome in early-onset nonfamilial nonpolyposis colorectal cancer.

Antelo M, Golubicki M, Roca E, Mendez G, Carballido M, Iseas S, Cuatrecasas M, Moreira L, Sanchez A, Carballal S, Castells A, Boland CR, Goel A, Balaguer F.

Int J Cancer. 2019 Aug 1;145(3):705-713. doi: 10.1002/ijc.32160. Epub 2019 Feb 23.

PubMed [citation]

PMID:: 30693488
PMCID:: PMC10423080

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001355296.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant changes 1 nucleotide in exon 12 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colon cancer whose tumor showed microsatellite instability and loss of MSH2 by immunohistochemistry (PMID: 30693488). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002717039.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The p.G614* pathogenic mutation (also known as c.1840G>T), located in coding exon 12 of the MSH2 gene, results from a G to T substitution at nucleotide position 1840. This changes the amino acid from a glycine to a stop codon within coding exon 12. This mutation has been reported in a 46 year old individual diagnosed with MSI colorectal cancer that exhibited loss of MSH2 and MSH6 proteins on immunohistochemistry (Antelo M et al. Int J Cancer, 2019 08;145:705-713). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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